Background

I am a post-doctoral research associate in the lab of Prof. Johannes Attems, and my current research interests lie in investigating the effects of multiple pathological lesions on clinical phenotype in neurodegenerative disorders (e.g. Alzheimer's disease and Lewy body disease). Using a quantitative clinico-patholigical approach we aim to tease is distinct clinico-pathologcal phenotypes which may ultimately lead to tailored treatment options for patients.

Research

Pyroglutamylated amyloid-beta

Recent data has suggested a subspecies of Aβ, termed ‘pyroglutamylated Aβ’ (pAβ), may play a crucial role in pathology. pAβ is more abundant in AD and is cytotoxic in the presence of hyperphosphorylated tau (HP-T). pAβ expression also correlates with the presence of HP-T and clinical dementia.

To further investigate the role of pAβ in AD and LBD we are currently using brain tissue from the Newcastle Brain Tissue Resource to quantitatively assess pAβ, HP-T and α-syn, and will compare the results with clinical findings. Using immunohistochemical and biochemical techniques we aim to correlate pAβ with neurofibrillary tangle development, and assess its potential role in synaptic injury and inflammatory response. In addition, we will compare pAβ expression in cerebrospinal fluid (CSF) with parenchymal deposits in the brain. The results will clarify if pAβ plays a crucial role in the pathogenesis of both AD and LBD. If so, pAβ may represent a potential biomarker in CSF and imaging diagnostics, and therapeutic target.

High throughput tissue microarray

Tissue microarray (TMA) is a technique most commonly employed in tumour studies, involving the extraction and transfer of a large number of samples into a single block, allowing high throughput analysis. This technique has previously been adapted to investigate white matter disease in human brain tissue, highlighting its potential use in dementia research. Our laboratory has developed a protocol to analyse 15 anatomically-distinct cortical and sub-cortical brain regions on one slide. Using an automated microscope and image analysis system we have accurately quantified a number of neuropathological lesions in human post-mortem brains from the Newcastle Brain Tissue Resource. Current analysis of over 150 cases has demonstrated a large variation of pathology load in patients with severe neurodegenerative diseases, which has not been appreciated using internationally recognised semi-quantitative staging criteria. This ongoing project will provide important information that can be used in clinico-pathological studies to assess the effect of single and multiple pathologies, on cognitive status.

TDP-43 in cerebral multi-morbidity

TDP-43 is the characteristic pathology of some types of motor neuron disease and frontal temporal dementia. However, recent studies have demonstrated TDP-43 is also found in Alzheimer's disease, where it follows a distinct topographic sequence of progression (Joseph et al, 2014; 2016). Using tissue from the Newcastle Brain Tissue Resource, we are currently investigating TDP-43 expression in other age-related neurodegenerative disorders.